Pharmacokinetics of a single dose of <i>Aficamten</i> (<scp>CK</scp>‐274) on cardiac contractility in a <scp>A31P</scp><i>MYBPC3</i> hypertrophic cardiomyopathy cat model

Sharpe, Ashley N.; Oldach, Maureen S.; Kaplan, Joanna L.; Rivas, Victor N.; Kovacs, Samantha L.; Hwee, Darren T.; Morgan, Bradley; Malik, Fady I.; Harris, Samantha P.; Stern, Joshua A.

doi:10.1111/jvp.13103

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…Cardiac myosin inhibitors, mavacamten and aficamten, have previously been evaluated in the same cat model 27 , 28 , 35 . Because each study was conducted under different experimental conditions, it is difficult to make direct comparisons between these three cardiac myosin inhibitors in this model.…”

Section: Discussionmentioning

confidence: 99%

“…Total CK-586 plasma concentrations were measured in a single batch by routine liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology as previously described 28 . Briefly, a 40 µL aliquot of each plasma was mixed with 120 µL of acetonitrile that contained N1-(butylcarbamoyl)-sulfanamide (0.1 µM) as the internal standard (retention time = 1.29 min).…”

Section: Methodsmentioning

confidence: 99%

“…We previously demonstrated successful acute dose-dependent (0.30- and 1.0 mg/kg) reductions in LV systolic function, left ventricular outflow tract maximum pressure gradient (LVOTmaxPG), and isovolumetric relaxation times (IVRT) after of a single oral gavage dose of aficamten in cats affected by asymptomatic oHCM harboring at least one copy of the feline A31P myosin-binding protein C3 ( MYBPC3 ) mutation 27 , 28 . Aficamten was well tolerated by all cats receiving treatment and successfully improved LVOTO.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy

Rivas,

Crofton,

Jauregui

et al. 2024

Sci Rep

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Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy

Rivas,

Crofton,

Jauregui

et al. 2024

Sci Rep

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“…HCM results from pathogenic genetic mutations, often affecting the genes encoding the proteins of the cardiac sarcomere, such as myosin ( Maron, 2018 ; Sharpe et al, 2023 ). Mechanistically, mutations in HCM appear to increase the net power generation in the sarcomere in vitro ( Chuan et al, 2012 ; Sommese et al, 2013 ; Spudich et al, 2016 ; Toepfer et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of aficamten in healthy Chinese participants: a randomized, double-blind, placebo-controlled, phase 1 study

Zhao,

Liu,

Tian

et al. 2023

Front. Pharmacol.

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Objectives: Aficamten is a selective, small-molecule allosteric inhibitor of cardiac sarcomere being developed as a chronic oral treatment for patients with symptomatic obstructive hypertrophic cardiomyopathy. This was the first-in-Chinese study aiming to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of aficamten in healthy adults.Methods: This double-blind, randomized, placebo-controlled, phase 1 study was conducted in 28 healthy male and female Chinese participants after single ascending dose (SAD) and multi-dose (MD) administrations of aficamten. In the SAD cohort, 16 participants were randomized to receive a single oral dose of aficamten: 10 mg, 20 mg, or placebo. In the MD cohort, 12 participants were randomized to receive multiple doses of aficamten: 5 mg or placebo once daily for 14 days. Safety was monitored throughout the study with electrocardiograms, echocardiograms, clinical laboratory tests, and reporting of adverse events (AEs). Pharmacokinetic profiles of aficamten and metabolites, as well as CYP2D6 genetic impact, were evaluated.Results: A total of 35 treatment-emergent AEs were reported by 14 (50%) participants with mild severity. There were no serious AEs or adverse decreases in left ventricular ejection fraction below 50% during the study. Aficamten was dose-proportional over the dose range of 5–20 mg and accumulated in the MD cohort.Conclusion: Aficamten was safe and well-tolerated in the healthy Chinese adult participants. The pharmacokinetics of aficamten in the Chinese population was comparable to those previously found in Western participants. These phase 1 data support the progression of aficamten into future clinical studies in Chinese patients.Clinical Trial registration:https://clinicaltrials.gov, identifier: NCT04783766.

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“…To date, direct treatment options for mitigating cardiac hypertrophy do not exist, however, limited therapies for treatment of the most sinister disease outcomes (e.g., left-sided congestive heart failure [CHF], thromboembolic events, and sudden cardiac death) are available in veterinary and human patients. Mitigation of left ventricular outflow tract obstruction in humans is achieved through the recent advent of myosin-inhibiting compounds [24][25][26][27]. Collectively, these data emphasize the need for a pharmaceutical compound to treat the primary feature of HCM (maladaptive LV hypertrophy) in veterinary and human patients alike.…”

Section: Introductionmentioning

confidence: 99%

Multi-Omic, Histopathologic, and Clinicopathologic Effects of Once-Weekly Oral Rapamycin in a Naturally Occurring Feline Model of Hypertrophic Cardiomyopathy: A Pilot Study

Rivas,

Kaplan,

Kennedy

et al. 2023

Animals

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Hypertrophic cardiomyopathy (HCM) remains the single most common cardiomyopathy in cats, with a staggering prevalence as high as 15%. To date, little to no direct therapeutical intervention for HCM exists for veterinary patients. A previous study aimed to evaluate the effects of delayed-release (DR) rapamycin dosing in a client-owned population of subclinical, non-obstructive, HCM-affected cats and reported that the drug was well tolerated and resulted in beneficial LV remodeling. However, the precise effects of rapamycin in the hypertrophied myocardium remain unknown. Using a feline research colony with naturally occurring hereditary HCM (n = 9), we embarked on the first-ever pilot study to examine the tissue-, urine-, and plasma-level proteomic and tissue-level transcriptomic effects of an intermittent low dose (0.15 mg/kg) and high dose (0.30 mg/kg) of DR oral rapamycin once weekly. Rapamycin remained safe and well tolerated in cats receiving both doses for eight weeks. Following repeated weekly dosing, transcriptomic differences between the low- and high-dose groups support dose-responsive suppressive effects on myocardial hypertrophy and stimulatory effects on autophagy. Differences in the myocardial proteome between treated and control cats suggest potential anti-coagulant/-thrombotic, cellular remodeling, and metabolic effects of the drug. The results of this study closely recapitulate what is observed in the human literature, and the use of rapamycin in the clinical setting as the first therapeutic agent with disease-modifying effects on HCM remains promising. The results of this study establish the need for future validation efforts that investigate the fine-scale relationship between rapamycin treatment and the most compelling gene expression and protein abundance differences reported here.

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Pharmacokinetics of a single dose of Aficamten (CK‐274) on cardiac contractility in a A31PMYBPC3 hypertrophic cardiomyopathy cat model

Cited by 8 publications

References 32 publications

Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy

Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy

Safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of aficamten in healthy Chinese participants: a randomized, double-blind, placebo-controlled, phase 1 study

Multi-Omic, Histopathologic, and Clinicopathologic Effects of Once-Weekly Oral Rapamycin in a Naturally Occurring Feline Model of Hypertrophic Cardiomyopathy: A Pilot Study

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